Nuclear factor-κB (NF-κB), a transcription factor critical to immune responses, is being recognized as an important signaling molecule in the pathogenesis of cancer, underscoring the plausible linkage between inflammation and carcinogenesis (M. Karin, Nature 441:431-436 (2006) and Z. Zhang, B. Rigas, Int. J. Oncol. 29:185-192 (2006)). NF-κB also plays a role in autoimmune responses, cell proliferation and apoptosis by regulating the expression of genes involved in these processes. The activity of NF-κB is tightly regulated by its interaction with inhibitor IκB proteins. In most resting cells, NF-κB (which is usually a heterodimer of p65/RelA and p50) is sequestered in the cytoplasm in an inactive form associated with inhibitory molecules such as IκBα, IκBβ, IκBγ, IκBε, p105 and p100. This interaction blocks the ability of NF-κB to bind to the κB binding site on DNA and thus to modulate gene expression. Following exposure to inflammatory cytokines, UV light, reactive oxygen species, bacteria or viral toxins, the NF-κB signaling cascade is activated, leading to the complete degradation of IκB. This allows for the translocation of unmasked NF-κB to the nucleus where it binds to the enhancer or promoter regions of target genes and regulates their transcription (K. J. Campbell, N. D. Perkins, Biochem. Soc. Symp. 73:165-180 (2006)).
The activation of NF-κB by extracellular inducers depends on the phosphorylation and subsequent degradation of IκB proteins. Activation of NF-κB is achieved through the action of a family of serine/threonine K kinases (IKK). The IKK contains two catalytic subunits (IKKα and IKKβ) and a regulatory/adapter protein NEMO (also known as IKKγ). IKKα and IKKβ phosphorylate IκB proteins and the members of the NF-κB family. All IκB proteins contain two conserved serine residues within their N-terminal area, which are phosphorylated by IKK. IKKα and IKKβ share about 50% sequence homology and can interchangeably phosphorylate Ser32/36 of IκBα, and Ser19/23 of IκBβ. These phosphorylation events lead to the immediate polyubiquitination of IκB proteins and rapid degradation by the 26S proteasome.
In the nucleus, acetylation of NF-κB determines its active or inactive state. Acetyltransferases play a major role in the acetylation of RelA/p65, principally targeting Lys 218, 221, 310 for modification. Acetylated NF-κB is active and is resistant to the inhibitory effects of IκB. However, when histone deacetylase 3 (HDAC3) deacetylates NF-κB, IκB readily binds to NF-κB and causes its translocation into the cytoplasm. Here HDAC3 serves as an intranuclear molecular switch that turns off the biological processes triggered by NF-κB. One of the target genes activated by NF-κB is that which encodes IκBα. Newly synthesized IκBα in the nucleus removes NF-κB from DNA, and exports the complex back to the cytoplasm to restore its original latent state.
The Rel/NF-κB signal transduction pathway is misregulated in a variety of human cancers, especially those of lymphoid cell origin. Several human lymphomas are reported to have mutations or amplifications of genes encoding NF-κB transcription factors. In most cancer cells NF-κB is constitutively active and resides in the nucleus. In some cases, this may be due to chronic stimulation of the IKK pathway, while in others the gene encoding IkBα may be defective. Such continuous nuclear NF-κB activity not only protects cancer cells from apoptotic cell death, but may even enhance their proliferation. Thus there remains a need for anti-tumor agents that block NF-κB activity or increase the sensitivity of tumors to conventional chemotherapy. There also remains a need for agents to block NF-κB activity to treat or prevent chronic inflammation or autoimmune disorders. The invention presented herein fulfills this need.